Biomarkers for Alzheimer's Disease

Alzheimer’s disease (AD) is an irreversible brain disorder that usually starts around the age of 65 years.

Three major brain defects which are associated with AD include formation of amyloid plaques – which are composed of beta-amyloid peptide fragments; neurofibrillary tangles – which are abnormal clusters of tau protein inside neurons; and loss of connection between neurones which are important for memory and learning.

Major signs and symptoms of AD include loss of memory, confusion, change in behavior and personality, and impaired decision-making and language skills. According to the recent estimation, about 13.8 million people are affected by AD worldwide.

Early-onset AD which generally starts between the age of 30 and 60 years, is caused by single-gene mutations on Chromosomes 21, 14, or 1. Each of these mutations ultimately leads to the formation of amyloid plaques, a hallmark of AD. It is relatively rare as compared to late-onset AD. The major genetic risk factor for late-onset AD is having ε4 variant of the apolipoprotein E (APOE) gene on Chromosome 19.

Biomarkers

Presently, the most common biomarkers which are estimated in the cerebrospinal fluid (CSF) to diagnose AD include beta amyloid protein, tau protein, and phospho-tau. These biomarkers have >95% sensitivity and >85% specificity to detect AD. Due to its direct contact with the brain and spinal cord, CSF is considered as an important biofluid to search for biochemical and metabolic biomarkers against AD. However, the need for painful and invasive lumber puncture technique to obtain CSF makes it difficult to use, as well as calls for identification of new biomarkers which can be obtained easily through non-invasive or minimally invasive techniques.

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To discover and establish new biomarkers for AD, researchers from around the world have set certain criteria. According to these criteria, an effective biomarker should have the following characteristics:

Reflect aging of brain

Describe pathophysiological processes in brain

Any pharmacological change should be reflected

Highly sensitive and specific

Reproducible results over time

Clear cut-off values with at least two-fold changes

Easily collectible results and inexpensive tests

Since the signs and symptoms of AD gradually increase over time, a regular follow-up is essential to effectively manage the disease outcome. To maintain a regular follow-up, it is important to search for biomarkers in easily collectible biofluids, such as blood, urine, and serum. To date, circulatory biomarkers which have been identified through various research findings include:

Circulatory microRNAs (miRNAs) – These are non-coding RNAs which regulate expressions of many genes through post-transcriptional gene silencing. Analysis of miRNA expression pattern in peripheral blood serves as a potential diagnostic method to detect AD. For instance, miRNAs which have shown down-regulated expressions in AD patients include miR-34a, miR-81b, and let-7f, just to name a few.

Amyloid beta in blood – Although it is an established biomarker in CSF, many studies have revealed that analysis of amyloid beta level in blood could serve as a potential new strategy to diagnose AD. In this context, measurement of high-performance plasma amyloid beta biomarkers by immunoprecipitation coupled with mass spectrometry has shown promising outcomes. However, further studies are needed to establish amyloid beta as a stable blood-based biomarker, as the plasma level of this protein differs with patient’s age, lifestyle, experimental conditions, and type of the assay.

Oxidative stress markers – Since increased production of free radicals is a characteristic feature of degenerated brain, markers of oxidative stress have the potential to be used for AD diagnosis. Some of these biomarkers include free fatty acids, protein nitration products, DNA oxidation products, lipid peroxidation products, 4-Hydroxy 2 trans Nonenal (HNE), and advanced glycation end-products.

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.

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